Time-dependent Fluctuations Research Articles

Rapid Estimation of Size-Based Heterogeneity in Monoclonal Antibodies by Machine Learning-Enhanced Dynamic Light Scattering.

Aggregation of monoclonal antibody therapeutics is a serious concern that is believed to impact product safety and efficacy. There is a need for analytical approaches that enable rapid estimation of mAb aggregates. Dynamic light scattering (DLS) is a well-established technique for estimating the average size of protein aggregates or for evaluating sample stability. It is usually used to measure the size and size distribution over a wide range of nano- to micro-sized particles using time-dependent fluctuations in the intensity of scattered light arising from the Brownian motion of particles. In this study, we present a novel DLS-based approach that allows us to quantify the relative percentage of multimers (monomer, dimer, trimer, and tetramer) in a monoclonal antibody (mAb) therapeutic product. The proposed approach uses a machine learning (ML) algorithm and regression to model the system and predict the amount of relevant species such as monomer, dimer, trimer, and tetramer of a mAb in the size range of 10-100 nm. The proposed DLS-ML technique compares favorably to all potential alternatives with respect to the key method attributes, including per sample cost of analysis, per sample time of data acquisition along with ML-based aggregate prediction (<2 min), sample requirements (<3 μg), and user-friendliness of analysis. The proposed rapid method can serve as an orthogonal tool to size exclusion chromatography, which is the current industry workhorse for aggregate assessment.

Exploring the Molecular Structural Requirements of Flavonoids as Beta- Secretase-1 Inhibitors Using Molecular Modeling Studies.

BACE1 (beta-site amyloid precursor protein (APP) cleaving enzyme) is a key target for Alzheimer's disease research because it catalyses the rate-limiting step in the formation of amyloid protein (Aβ). Natural dietary flavonoids have gained a lot of interest as potential Alzheimer's therapy candidates because of their anti-amyloidogenic, antioxidative, and anti-inflammatory properties. More research is needed, however, to learn more about the specific routes through which flavonoids may have neuroprotective benefits in Alzheimer's disease. Here, we report an in silico molecular modeling study for natural compounds, particularly flavonoids, as BACE-1 inhibitors. The interactions of flavonoids with the BACE-1 catalytic core were disclosed by demonstrating the predicted docking pose of flavonoids with BACE-1. The stability of flavonoids BACE-1 complex was analyzed by molecular dynamic simulation (standard dynamic cascade). Our findings imply that these flavonoids, which have methoxy group instead of hydroxy may be promising BACE1 inhibitors that could reduce Aβ formation in Alzheimer's disease. The molecular docking study revealed that flavonoids e bind with the BACE1's wide active site along with the catalytic residues Asp32 and Asp228. Further molecular dynamic investigation revealed that the average RMSD for all complexes ranged from 2.05 to 2.32 Å, indicating that the molecules were relatively stable during MD simulation. The RMSD analyses demonstrate that the flavonoids were structurally stable during the MD simulation. The RMSF was utilised to study the time-dependent fluctuation of the complexes. The N-terminal (~2.5 Å) fluctuates less than the C-terminal (~6.5 Å). Rutin and Hesperidin were highly stable in the catalytic region as compared to other flavonoids like Rhoifolin, Hesperidin, Methylchalcone, Phlorizin and Naringin. We were able to justify the flavonoids' selectivity for BACE-1 and crossing BBB for the treatment of Alzheimer's disease by using a combination of molecular modelling tools.

Dynamics of Taylor bubble interface in vertical turbulent counter-current flow

Dynamics of the Taylor bubble interface in the vertical counter-current flow was analyzed with video recordings at 100 – 800 frames per second. Taylor bubbles in air-water mixture were studied on time intervals of up to several minutes in stagnant conditions, where buoyancy is dynamically balanced by the inertial bubble drag in the downward turbulent flow. Taylor bubbles of length from 4 to 10 cm were observed in a pipe of 26 mm diameter at Reynolds numbers based on liquid superficial velocity around 6000. Algorithms, developed for analysis of the interface from the video frames were dedicated to the analysis of the cap and the body of the Taylor bubble. The long time averaging of up to 10 min samples do not end up with axisymmetric time-averaged shape of the bubble, but with an asymmetric bullet-train shape, with the thinnest liquid film observed on the belly of the bullet-train shape bubble. The main result of this study is based on high relative sensitivity of our measurements, which was sufficient to track the dynamics of the tiny disturbance waves with a tenth of mm amplitudes traveling along the interface of the Taylor bubble. Cross-correlations of time-dependent interface fluctuations measured at different spatial positions allowed us to measure propagation speeds of the interface waves. When averaged over sufficiently long time intervals of around a minute, the time averaged propagation velocities are shown to be equal to the convective velocity of the interface. Moreover, waves propagating on both sides of the two-dimensional photographs show clear correlation; crest of the wave on one side of the bubble photograph corresponds to the trough of the wave on the other side.

Atomistic simulation of protein evolution reveals sequence covariation and time-dependent fluctuations of site-specific substitution rates.

Thermodynamic stability is a crucial fitness constraint in protein evolution and is a central factor in shaping the sequence landscapes of proteins. The correlation between stability and molecular fitness depends on the mechanism that relates the biophysical property with biological function. In the simplest case, stability and fitness are related by the amount of folded protein. However, when proteins are toxic in the unfolded state, the fitness function shifts, resulting in higher stability under mutation-selection balance. Likewise, a higher population size results in a similar change in protein stability, as it magnifies the effect of the selection pressure in evolutionary dynamics. This study investigates how such factors affect the evolution of protein stability, site-specific mutation rates, and residue-residue covariation. To simulate evolutionary trajectories with realistic modeling of protein energetics, we develop an all-atom simulator of protein evolution, RosettaEvolve. By evolving proteins under different fitness functions, we can study how the fitness function affects the distribution of proposed and accepted mutations, site-specific rates, and the prevalence of correlated amino acid substitutions. We demonstrate that fitness pressure affects the proposal distribution of mutational effects, that changes in stability can largely explain variations in site-specific substitution rates in evolutionary trajectories, and that increased fitness pressure results in a stronger covariation signal. Our results give mechanistic insight into the evolutionary consequences of variation in protein stability and provide a basis to rationalize the strong covariation signal observed in natural sequence alignments.

Dynamic hosting capacity of photovoltaic system analysis and enhancement using distributed SVC and STATCOM compensators: Case study of a university building

This paper presents a comprehensive approach for dynamically estimating the hosting capacity of photovoltaic (PV) systems. The proposed method takes into account time-dependent fluctuations of generation and load, as well as overvoltage constraints, in its mathematical model. A set of weekly measurements taken every minute from a low-voltage side of a university building in Morocco were analyzed to show load variations.The proposed approach is compared to a static method to demonstrate its effectiveness. The results show that the voltage increases after PV integration, but does not cause overvoltage, even in the worst-case scenario where generation exceeds load demand. To address voltage fluctuations, the use of Static VAr Compensators (SVC) and Static Synchronous Compensators (STATCOM) in distribution systems was compared. The simulation results indicated that STATCOM was more effective than SVC in mitigating voltage fluctuations, resulting in an improvement of the PV hosting capacity.

Theoretical Tools to Quantify Stochastic Fluctuations in Single-Molecule Catalysis by Enzymes and Nanoparticles.

Single-molecule microscopic techniques allow the counting of successive turnover events and the study of the time-dependent fluctuations of the catalytic activities of individual enzymes and different sites on a single heterogeneous nanocatalyst. It is important to establish theoretical methods to obtain the statistical measurements of such stochastic fluctuations that provide insight into the catalytic mechanism. In this review, we discuss a few theoretical frameworks for evaluating the first passage time distribution functions using a self-consistent pathway approach and chemical master equations, to establish a connection with experimental observables. The measurable probability distribution functions and their moments depend on the molecular details of the reaction and provide a way to quantify the molecular mechanisms of the reaction process. The statistical measurements of these fluctuations should provide insight into the enzymatic mechanism.

Time course of plasticity-related alterations following the first exposure to amphetamine in juvenile rats

In vulnerable consumers, the first drug exposure induces various neurobehavioral adaptations that may represent the starting point toward addiction. Elucidating the neuroplastic mechanisms underlying that first rewarding experience would contribute to understanding the transition from recreational to compulsive drug use. In a preclinical model with juvenile rats, we analyzed the time-dependent fluctuations in the expression of neuroplasticity-related genes like the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and the neurotransmitters contents in the nucleus accumbens (NAc) and the dorsal striatum (DS) 45, 90, and 180 min after an amphetamine (AMPH) injection. As expected, AMPH altered the concentration of norepinephrine, dopamine, DOPAC, and serotonin in a region- and time-dependent manner. Regarding gene expression, AMPH at 45 min upregulated BDNF and primiR-132 expression in NAc and downregulated TrkB expression in DS. At 90 min, AMPH upregulated TrkB, CREB, p250GAP, and primiR-132 expression in NAc and BDNF, primiR-132, and CRF in DS. At 180 min, only BNDF in NAc continued to be upregulated by AMPH. Based on the levels of AMPH-induced hyperactivity, we classified the rats as low and high AMPH responders. High AMPH responders characterized by overexpressing BDNF, CREB, p250GAP, and CRF in NAc and by showing lower levels of dopamine and serotonin metabolites and turnovers in both regions. Our findings demonstrated that a single AMPH administration is enough to induce neuroplastic adaptations, especially in the NAc of prone rats.

Ion kinetic effects and instabilities in the plasma flow in the magnetic mirror

Kinetic effects in plasma flow due to a finite ion temperature and ion reflections in a converging–diverging magnetic nozzle are investigated with collisionless quasineutral hybrid simulations with kinetic ions and isothermal Boltzmann electrons. It is shown that in the cold ions limit, the velocity profile of the particles agrees well with the analytical theory, predicting the formation of the global accelerating potential due to the magnetic mirror with the maximum of the magnetic field and resulting in the transonic ion velocity profile. The global transonic ion velocity profile is also obtained for warm ions with isotropic and anisotropic distributions. Partial ion reflections are observed due to a combined effect of the magnetic mirror and time-dependent fluctuations of the potential as a result of the wave breaking and instabilities in the regions when the fluid solutions become multi-valued. Despite partial reflections, the flow of the passing ions still follows the global accelerating profile defined by the magnetic field profile. In simulations with reflecting boundary condition imitating the plasma source and allowing the transitions between trapped and passing ions, the global nature of the transonic accelerating solution is revealed as a constrain on the plasma exhaust velocity that ultimately defines plasma density in the source region.

A critical analysis of the CFD-DEM simulation of pharmaceutical aerosols deposition in extra-thoracic airways

Recent advances in the characterization of the human respiratory system and in multi-phase flow dynamics in complex geometries have led numerical simulations to play an expanding role for exploring aerosol deposition mechanisms in the lungs. However, the development of an efficient numerical and mathematical description is far from unique, and determining which aspects of the modelling are critical and which details are essentially irrelevant is indeed a difficult task. With the aim of addressing this lack of a rationalized framework, we propose a systematic analysis of pharmaceutical aerosols deposition in the extra-thoracic airways, focusing on several important modelling aspects whose related assumptions and approximations have not always been sufficiently discussed and clarified. We consider the importance of intrinsic time dependent fluctuations of the air flow, highlighting how their contribution in aerosol deposition is as important as the particle-turbulence interaction one. We show how sensitive the turbulence intensity can be to the meshing strategy and how aerosol deposition can be influenced by the latter choice. We demonstrate how a swirling air jet can enhance extra-thoracic deposition compared to a straight one, and how different the deposition patterns can be in case a realistic inhalation profile and aerosol plume are employed.

Comparison of measured strain and thermal effects during reactor building leakage rate tests of a nuclear power plant

With nuclear reactor power plants, Reactor Building (RB) Leak-Rate Tests (LRTs) are conducted at regular intervals to confirm the air leak tightness of a containment structure. These LRTs provide an excellent opportunity to study the containment structure’s behaviour when subjected to internal pressure, thereby evaluating the structural performance of the containment structure. However, significant time-dependent fluctuations are observed in the measured strains due to the contribution of thermal strain induced by the surrounding environment. In order to accurately study the mechanical behavior of the containment structure, the thermal strain must be separated from the measured total strain. In this study, environmental data was collected during an RB LRT. Finite element analyses were carried out by utilizing the environmental conditions to predict the thermal strain of the containment structure. The predicted thermal strain was then subtracted from the measured total strain, so the underlying mechanical strain induced by the internal pressure could be approximated. The mechanical behavior of a containment structure during LRTs over an eighteen-year period is compared to understand the overall aging effects of a CANDU®11CANDU (CANada Deuterium Uranium Reactor) is a registered trademark of the Atomic Energy of Canada Limited (AECL), used under exclusive license by Candu Energy Inc. containment structure. Only a slight change in structural stiffness was observed over eighteen years though further study is suggested to confirm this. This paper outlines how field data collected during LRTs can be used to provide insight into understanding the long-term behavior of a containment structure.

Parrondo’s Paradox for Discrete-Time Quantum Walks in Momentum Space

We investigate the possibility of implementing a sequence of quantum walks whose probability distributions give an overall positive winning probability, while it is negative for the single walks (Parrondo’s paradox). In particular, we have in mind an experimental realization with a Bose–Einstein condensate in which the walker’s space is momentum space. Experimental problems in the precise implementation of the coin operations for our discrete-time quantum walks are analyzed in detail. We study time-dependent phase fluctuations of the coins as well as perturbations arising from the finite momentum width of the condensate. We confirm the visibility of Parrondo’s paradox for experimentally available time scales of up to a few hundred steps of the walk.

Gravure Printing for PVDF Thin-Film Pyroelectric Device Manufacture

Pyroelectric energy harvesting is one of the more recent and promising solid-state approaches for directly converting time-dependent temperature fluctuations into electric energy. Conventional printing technologies can offer many advantages for the production of pyroelectric thin-film-based devices, such as low cost, low temperature, the use of flexible substrates and shaping at the same time as deposition. Nevertheless, some issues related to low printed thickness and film-forming microstructure control need to be addressed. In this exploratory study, the possibility of exploiting the highly attractive gravure printing process for the potential industrial manufacture of flexible polyvinylidene fluoride (PVDF) thin-film pyroelectric devices was investigated. By the use of corona pre-treatment of the printing substrate and low-temperature polar solvent evaporation, multilayer gravure-printed PVDF pyroelectric devices were successfully manufactured for the first time, achieving a maximum generated current of 0.1 nA at 2.5 K/s from a device with an active area of 1 cm2. Considering the very low thermal inertia and performance scaling by the area expected for pyroelectric thin-film-based devices, combined with the upscaling potential of roll-to-roll gravure printing, our results provide new opportunities for on-demand, low-cost pyroelectric device manufacture and their integration in hybrid harvesters.

Utilizing single light-emitting-diode (LED) lamp and silicon solar-cells visible light positioning (VLP) based on angle-of-arrival (AOA) and long-short-term-memory-neural-network (LSTMNN)

We propose and present the first proof-of-concept demonstration of an angle-of-arrival (AOA)-based visible-light-positioning (VLP) system using long-short-term-memory neural-network (LSTMNN) model. Only a single LED lamp and silicon based solar cell Rx are needed. The LSTM cell can manipulate and analyze time-serial sequential data, reducing the influence of time-dependent fluctuation and noises during the AOA data acquisition; hence, enhancing the positioning accuracy. We compare different ML models including the linear regression (LR) and artificial neural network (ANN), as well as different AOA data sequence lengths and additional LSTM layers. The experimental result reveals that the LSTMNN model outperforms the other models under evaluation. When the sequence length of 20 and one LSTM layer are employed, the mean positioning error is 1.78 cm and the 90% of the experimental data has positioning error within ∼2.9 cm. Compared to the LR model and ANN model, the mean positioning errors are reduced by 49% and 40% respectively; and the 90% cumulative distribution function (CDF) values are reduced by 3 cm and 1.3 cm respectively by utilizing the proposed LSTMNN model.

Time of day-dependent deviations in dynamic and static occlusion: A prospective clinical study

Statement of problemThe registration of dental occlusion is essential for prosthodontic treatment. However, studies on time-dependent changes of static and dynamic occlusion that may affect definitive restorations are lacking. PurposeThe purpose of this prospective clinical study was to use conventional and digital occlusal registration techniques to evaluate time-dependent fluctuations in static and dynamic occlusion. Material and methodsThe static and dynamic occlusion of 19 healthy individuals (14 women and 5 men with a mean ±standard deviation age of 30.8 ±4.8 years) was examined 3 times a day using occlusal foil (12-μm occlusion foil) and a digital sensor (T-Scan III). The procedure was repeated after 14 days. The statistical analysis covered all registrations referencing the first measurement point to assess occurring differences, and changes per tooth and arch were determined (α=.05). Potential influencing factors were calculated by using mixed logistic regression. Marginal probabilities were calculated considering the registration technique and the time of measurement. ResultsSignificant differences were found between registered occlusal patterns and the different registration techniques. Occlusal changes per maxillary dental arch were observed with static foil registration (P<.001; 98.8%), left laterotrusion foil registration (P=.001; 29.6%), right laterotrusion foil registration (P=.001; 29.6%), static sensor registration (P<.001; 20.3%), left laterotrusion sensor registration (P=.001; 71.7%), and right laterotrusion sensor registration (P=.005; 67.7%). None of the techniques showed higher probabilities of occlusal changes at a given time of day with respect to time-dependent changes. ConclusionsThe study revealed that occlusion cannot be considered constant and that the topography and intensity of the contact points vary. Circadian occlusion variance can be assumed without preferring a specific time of the day. This differentiated view of occlusion as a changing system helps to clarify the challenge of dental restorations for both the patient and the practitioner.

Superfluid transition temperature and fluctuation theory of spin-orbit- and Rabi-coupled fermions with tunable interactions

We obtain the superfluid transition temperature of equal Rashba-Dresselhaus spin-orbit- and Rabi-coupled Fermi superfluids, from the Bardeen-Cooper-Schrieffer (BCS) to Bose-Einstein condensate (BEC) regimes in three dimensions for tunable $s$-wave interactions. In the presence of Rabi coupling, we find that spin-orbit coupling enhances (reduces) the critical temperature in the BEC (BCS) limit. For fixed interactions, we show that spin-orbit coupling can convert a first-order (discontinuous) phase transition into a second-order (continuous) phase transition, as a function of Rabi coupling. We derive the Ginzburg-Landau free energy to sixth power in the superfluid order parameter to describe both continuous and discontinuous phase transitions as a function of spin-orbit and Rabi couplings. Lastly, we develop a time-dependent Ginzburg-Landau fluctuation theory for an arbitrary mixture of Rashba and Dresselhaus spin-orbit couplings at any interaction strength.

An alternative, dynamic density functional-like theory for time-dependent density fluctuations in glass-forming fluids.

We propose an alternative theory for the relaxation of density fluctuations in glass-forming fluids. We derive an equation of motion for the density correlation function that is local in time and is similar in spirit to the equation of motion for the average non-uniform density profile derived within the dynamic density functional theory. We identify the Franz-Parisi free energy functional as the non-equilibrium free energy for the evolution of the density correlation function. An appearance of a local minimum of this functional leads to a dynamic arrest. Thus, the ergodicity breaking transition predicted by our theory coincides with the dynamic transition of the static approach based on the same non-equilibrium free energy functional.

Conductance of correlated many-fermion systems from charge fluctuations

We put forward a relation between the static charge fluctuations and the conductance of correlated many-fermion systems at zero temperature, avoiding the use of time-dependent fluctuations as in the fluctuation-dissipation theorem. Static charge fluctuations can efficiently be computed for low-dimensional systems using tensor network approaches, while the conductance is often significantly more difficult to obtain, requiring a challenging low-frequency linear response computation or an explicit time evolution. We put this relation to the test for quantum dot and quantum point contact setups, where in limiting cases exact results are known. Our study includes systems in which the one-dimensional reservoirs are interacting.

Identification of topological measures of visibility graphs for analyzing transitions in complex time series

In this paper, we investigate signatures of variation in the behavior of correlated time series by analyzing changes in the topological properties of the corresponding visibility graph. Variations in six different network measures: assortativity, average path length, clustering, transitivity, density, and the average of the mean link length, are explored. We construct visibility graphs from the original and the magnitude and sign of its increment series. Both the horizontal and the natural visibility graphs are studied. Through extensive numerical studies on the time series of fractional Brownian motion (fBm), we first identify network measures that can reflect the changes in correlations in the time series. The efficacy of these markers is examined to identify the transitions in two systems, a two-dimensional (2D) Ising spin system and EEG data with seizures. While all the identified network measures capture the change in the thermal equilibrium correlations for the Ising spin system, they have limited success in the case of the time-dependent fluctuations in the EEG data. We identify some markers relevant to detecting seizures in the EEG data set.

Time dependent fluctuations of linear eigenvalue statistics of some patterned matrices

We consider the n × n reverse circulant and symmetric circulant random matrices with independent Brownian motion entries. With polynomial test functions ϕ, we discuss the joint fluctuation and tightness (in t and ϕ) of the time dependent linear eigenvalue statistics of these matrices as n → ∞ and show convergence to appropriate Gaussian processes. The proofs are mainly combinatorial.

Real-time calibrating polarization-sensitive diffuse reflectance handheld probe characterizes clinically relevant anatomical locations of oral tissue in vivo.

We report on the development of a unique real-time calibrating polarization-sensitive diffuse reflectance (rcPS-DR) handheld probe, and demonstrate its diagnostic potential through in-depth characterization and differentiation of clinically relevant anatomical locations of the oral cavity (i.e., alveolar process, lateral tongue and floor of mouth that account for 80% of all cases of oral squamous cell carcinoma) in vivo. With an embedded calibrating polytetrafluoroethylene (PTFE) optical diffuser, the PS-DR spectra bias arising from instrument response, time-dependent intensity fluctuation and fiber bending is calibrated through real-time measurement of the PS-DR system response function. A total of 554 in vivo rcPS-DR spectra were acquired from different oral tissue sites (alveolar process, n = 226, lateral tongue, n = 150 and floor of mouth, n = 178) of 14 normal subjects. Significantly (P<0.05, unpaired 2-sided Student's t-test) different spectral ratio (I 540/I 575) representing oxygenated hemoglobin contents were found among the alveolar process, lateral tongue and floor of mouth. Further partial least squares discriminant analysis (PLS-DA) and leave-one-out, cross validation (LOOCV) show that, synergizing the complementary information of the two real-time calibrated orthogonal-polarized PS-DR spectra, the rcPS-DR technique is found to better differentiate alveolar process, lateral tongue, and the floor of mouth (accuracies of 88.2%, 83.9%, 84.4%, sensitivities of 80.5%, 75.8%, 78% and specificities of 93.5%, 87.7%, 86.8%) than standard DR (accuracies of 80.8%, 72.9%, 68.5%, sensitivities of 63.2%, 41.5%, 81.3% and specificities of 92.9%, 87.7%, 63.8%) without PS detection. This work showed the feasibility of the rcPS-DR probe as a tool for studying oral cavity lesions in real clinical applications.